Loss of breast epithelial marker hCLCA2 promotes epithelial-to-mesenchymal transition and indicates higher risk of metastasis.
Loss of breast epithelial marker hCLCA2 promotes epithelial-to-mesenchymal transition and indicates higher risk of metastasis.
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DOI：
10.1038/onc.2011.392
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发表时间：
2012-04-26
期刊：
影响因子：
8
通讯作者：
Elble, R. C.
中科院分区：
文献类型：
--
作者：
Walia, V.;Yu, Y.;Cao, D.;Sun, M.;McLean, J. R.;Hollier, B. G.;Cheng, J.;Mani, S. A.;Rao, K.;Premkumar, L.;Elble, R. C.
上皮和间质状态之间的转换是正常发育和肿瘤进展的特征。我们报告说，表达的氯离子通道辅助蛋白hCLCA 2是上皮分化的永生化MCF 10A和HMLE模型的一个特点，而诱导EMT细胞稀释，TGF β，或间充质转录因子急剧降低hCLCA 2水平。通过慢病毒shRNA减弱hCLCA 2表达导致细胞过度生长和病灶形成，增强迁移和侵袭，并增加甲基纤维素中的乳腺球形成。这些变化伴随着E-钙粘蛋白的下调和间充质标志物如波形蛋白和纤连蛋白的上调。此外，hCLCA 2表达在具有间充质或紧密连接蛋白低分布的乳腺癌细胞中大大下调。这些观察结果表明，hCLCA 2的损失可能会促进转移。我们发现，hCLCA 2表达高于中位数与乳腺癌患者18年内转移率降低三分之一相关，而低于中位数（n=344，未筛选亚型）。因此，hCLCA 2是上皮分化所必需的，并且其在肿瘤进展期间的丢失有助于转移。已报道hCLCA 2的过表达抑制细胞增殖，并伴随着质膜处的氯电流增加和细胞内pH（pHi）降低。我们发现，敲低细胞具有急剧降低的氯电流和较高的pHi，这两种肿瘤细胞的特征。这些结果提示了影响分化的机制。hCLCA 2的丢失可能会使pHi稳态机制逃逸，从而使细胞内pH值升高，细胞外pH值降低，这是侵袭性肿瘤细胞的特征。
Transition between epithelial and mesenchymal states is a feature of both normal development and tumor progression. We report that expression of chloride channel accessory protein hCLCA2 is a characteristic of epithelial differentiation in the immortalized MCF10A and HMLE models, while induction of EMT by cell dilution, TGFbeta, or mesenchymal transcription factors sharply reduces hCLCA2 levels. Attenuation of hCLCA2 expression by lentiviral shRNA caused cell overgrowth and focus formation, enhanced migration and invasion, and increased mammosphere formation in methylcellulose. These changes were accompanied by downregulation of E-cadherin and upregulation of mesenchymal markers such as vimentin and fibronectin. Moreover, hCLCA2 expression is greatly downregulated in breast cancer cells with a mesenchymal or claudin-low profile. These observations suggest that loss of hCLCA2 may promote metastasis. We find that higher-than-median expression of hCLCA2 is associated with a one-third lower rate of metastasis over an 18 year period among breast cancer patients compared to lower-than-median (n=344, unfiltered for subtype). Thus, hCLCA2 is required for epithelial differentiation, and its loss during tumor progression contributes to metastasis. Overexpression of hCLCA2 has been reported to inhibit cell proliferation and is accompanied by increases in chloride current at the plasma membrane and reduced intracellular pH (pHi). We found that knockdown cells have sharply reduced chloride current and higher pHi, both characteristics of tumor cells. These results suggest a mechanism for the effects on differentiation. Loss of hCLCA2 may allow escape from pHi homeostatic mechanisms, permitting the higher intracellular and lower extracellular pH that are characteristic of aggressive tumor cells.
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影响因子：
10.5
作者：
Dontu, G;Abdallah, WM;Wicha, MS
通讯作者：
Wicha, MS
DOI：
10.1113/jphysiol.2009.170159
发表时间：
2009-05-15
期刊：
The Journal of physiology
影响因子：
--
作者：
Hamann M;Gibson A;Davies N;Jowett A;Walhin JP;Partington L;Affleck K;Trezise D;Main M
通讯作者：
Main M
影响因子：
12.4
作者：
Kogan-Sakin, I.;Tabach, Y.;Rotter, V.
通讯作者：
Rotter, V.
影响因子：
2.5
作者：
Creighton, Chad J.;Chang, Jenny C.;Rosen, Jeffrey M.
通讯作者：
Rosen, Jeffrey M.
影响因子：
5.2
作者：
D'Assoro AB;Leontovich A;Amato A;Ayers-Ringler JR;Quatraro C;Hafner K;Jenkins RB;Libra M;Ingle J;Stivala F;Galanis E;Salisbury JL
通讯作者：
Salisbury JL